The mechanisms of nephrotoxicity, hepatotoxicity, hemolysis, methemoglobinemia, and carcinogenesis of N-arylacetamide are believed to occur through metabolism. The key metabolite in each of these toxicities has been postulated to be the N-hydroxy derivative. N-hydroxylation of the analgesic acetaminophen is believed to produce hepatotoxic metabolites. N-hydroxylation of polycyclic N-arylacetamides followed by N-O-sulfation is believed to produce the ultimate carcinogenic metabolite of these compounds. Since we have previously shown that the analgesic phenacetin and related compounds are readily N-hydroxylated, we have examined the capacity of these compounds to be sulfated and glucuronidated. Thus N-hydroxyphenacetin is readily sulfated to form an electrophilic metabolite which covalently binds to macromolecules. This compound is also glucuronidated to form an electrophilic metabolite. Other phenacetin analogs were also sulfated and glucuronidated but the metabolites were not electrophilic. The conditions for the activation and the detoxification of these reactive metabolites have been studied.